Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals  

作　　者：XUELIANG WU SHAOYU GUAN YONGGANG LU JUN XUE XIANGYANG YU QI ZHANG XIMO WANG TIAN LI 

机构地区：[1]Department of Gastrointestinal Surgery,Tianjin Medical University Nankai Hospital,Tianjin,300100,China [2]93868 Troop of the Chinese People’s Liberation Army,Yinchuan,750021,China [3]Clinical Laboratory,Hebei General Hospital,Shijiazhuang,050051,China [4]Department of General Surgery,The First Affiliated Hospital of Hebei North University,Zhangjiakou,075000,China [5]Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair,Institute of Integrative Medicine for Acute Abdominal Diseases,Integrated Chinese and Western Medicine Hospital,Tianjin University,Tianjin,300100,China [6]School of Basic Medicine,Fourth Military Medical University,Xi’an,710032,China

出　　处：《Oncology Research》2023年第2期125-139,共15页肿瘤学研究（英文）

基　　金：Natural Science Foundation Project of Hebei Province(H2022405033).

摘　　要：This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase(SHP-2)on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2(Tie2)-expressing monocyte/macrophages(TEMs)and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)(Ang/Tie2-PI3K/Akt/mTOR)signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment.In vivo,SHP-2-deficient mice were used to construct colorectal cancer(CRC)liver metastasis models.SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice,and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages’specific SHP-2-deficient mice(SHP-2MACKO)+planted tumor mice.Compared with the SHP-2 wild type mice(SHP-2WT)+planted tumor group,the SHP-2MAC-KO+planted tumor group experienced increased expression of p-Tie2,p-PI3K,p-Akt,p-mTOR,vascular endothelial growth factor(VEGF),cyclooxygenase-2(COX-2),matrix metalloproteinase 2(MMP2),and MMP9 in the liver tissue.TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers.It was found that when Angpt1/2 was used for stimulation,the SHP-2MAC-KO+Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway.The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT+Angpt1/2 group,while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2+Neamine.To sum up,the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs,thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.

关 键 词：SHP-2 TIE2 PI3K Akt/mTOR signaling Colorectal cancer Liver metastasis MACROPHAGES 

分 类 号：R735.3[医药卫生—肿瘤]